PROJECT SUMMARY/ABSTRACT Diseases of the macula, a primate-specific retinal specialization that is critical for high acuity vision, are a leading cause of vision loss worldwide. Animal models are essential for resolving macular disease mechanisms and testing treatments. Non-human primates, which are favored as models because they possess a macula, require decades to develop and are costly to maintain. Dogs and pigs have also been considered, but a macula-related structure that recapitulates features of macular disease has been reported only in dogs, and studies of these animals are also limited by time and cost. Laboratory mice can be bred and analyzed much more efficiently than large animals, but their use in macular disease research is often criticized due to the view that mice lack a macula-related structure. In preliminary studies that challenge this view, raised hyaline lesions in the retinal pigment epithelium (RPE) of a homozygous mutant Ctnna1 mouse model of butterfly-shaped pigment dystrophy were distributed in a dorsal band with a temporal bias. A similar band of subtle lesions in or near the RPE was observed with age in fundus images of heterozygous Ctnna1 mutant mice, which have milder disease. This distribution parallels a dorsal-temporal feature of the mouse retina characterized by photoreceptor and ganglion cell density gradients, as in the human macula. The central hypothesis is that this area of the mouse posterior eye constitutes a macula-related retinal specialization that develops lesions under conditions linked to human macular disease. To test this hypothesis, we will 1) determine the topographic distribution of hyaline RPE lesions in homozygous Ctnna1 mutant mice, the structure of the retina in the vicinity of these lesions, and the RPE and retinal structure of the corresponding region in wild-type mice by noninvasive imaging and microscopy; and 2) examine whether subtle RPE lesions occur with a similar topographic distribution in aging heterozygous Ctnna1 mutants and in wild-type mice. To achieve these aims, we will use a new approach to register images of the mouse posterior eye in spherical geometry based on vascular landmarks. These studies are expected to define a macula-related structure in mice that is targeted by gene- and age-dependent pathogenic processes. !